One of the approaches applied in the last decade for extending the actions of short-lived peptide/protein drugs is to endow them with affinity to serum albumin. This has been achieved by the covalent linking of ligands that bind albumin such as long-chain fatty acids (LCFAs) or bile acids (Kurtzhals et al., 1995; Jonassen et al., 2006; Rolin et al., 2002; Son et al., 2009; Chae et al., 2010). This approach leads to significant elevation in the hydrophobic character of those peptide/protein derivatives and a modest elevation in their affinity towards serum albumin. Bile acids have low association affinity to albumin (Roda et al., 1982) and have considerably lower affinity after linkage to a peptide or a protein. LCFAs such as palmitate associate tightly with albumin, but negligibly if covalently linked via their carboxylate moiety (Peters, 1996; Carter and Ho, 1994). Elevating hydrophobicity of peptide and protein drugs may increase their antigenicity and reduce their bioavailability after subcutaneous administration. Correspondingly, this can alter their pharmacokinetic/pharmacodynamic patterns in an undesirable fashion (Goodman and Gilman, 1995).
Insulin-detemir (Levemir®, NovoNordisk) is a long-acting insulin analog in which LCFA-like probe is integrated into the insulin molecule (Kurtzhals et al., 1995, 1996, 1997). More particular, it is an insulin analog in which the amino acid threonine in position B30 is omitted and myristic acid has been attached to the amino acid lysine in position B29 via the acyl group, i.e., NεB29-tetradecanoyl des(B30) insulin. In the blood, insulin-detemir binds to albumin through the alkyl residue of the myristic acid and it is then slowly dissociated from this complex. Insulin detemir as well as other similar derivatives of insulin are disclosed in U.S. Pat. Nos. 5,750,497, 6,011,007 and 6,869,930, and in US Patent Publication Nos. 20040110664 and 20060030518. These publications disclose an insulin derivative in which (i) the amino acids at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; (ii) the amino acid at position B1 is Phe or is deleted; (iii) the amino acid at position B30 is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys, or is deleted; and (iv) the amino ε-amino group of LysB29 is substituted with an acyl group having at least 10 carbon atoms or a lipophilic substituent having at least 6 carbon atoms, wherein the insulin derivative is a Zn2+ complex that is more water soluble than the insulin derivative without Zn2+. The technology disclosed in these publications is directed to insulin derivatives only, wherein the lipophilic substituent is linked to the insulin derivative via an amino group on the insulin molecule, preferably the ε-amino of the amino acid lysine at position B29, and the insulin derivative is bound to albumin, upon administration, mainly via binding groups present in the albumin molecule capable of binding aliphatic chains.
U.S. Pat. No. 7,186,797 discloses polypeptide conjugates having extended half life in vivo, comprising a polypeptide conjugated to a binding moiety having affinity for albumin. The binding moiety disclosed has two arms, wherein each one of these arms binds to albumin via a certain linking group that is either an aryl moiety or a non-aromatic moiety having 1-10 carbon atoms.
WO 2008/053360 discloses portable albumin binders, capable of binding to albumin through a functional group that is negatively charged or may be deprotonated to yield a negative charge, e.g., a carboxyl group, which are said to be useful for improving the pharmacokinetic properties of diagnostic or therapeutic agents, e.g., by increasing their circulation lifetime.
WO 2005/117984 discloses compounds consisting essentially of a spacer group, a water-soluble bridging group, a fatty acid chain, and an acidic group, preferably carboxyl, phosphonic, phosphinic, sulphinic or sulphonic group, attached to the distal end of said fatty acid chain. As stated in this publication, these compounds are capable of binding to albumin more effectively than such compounds without said acidic group, and are thus used for extending the in vivo serum half-life of proteins or peptides conjugated thereto.
WO 2010/015668 discloses conjugates comprising a protein or glycoprotein such as a blood coagulation factor linked to one or more units each consisting of an albumin binding residue, which is a lipophilic residue negatively charged at physiological pH and capable of non-covalently binding to albumin, linked through a hydrophilic spacer to said protein or glycoprotein. As stated in this publication, the albumin binding residue may be, inter alia, a residue comprising ω-carboxylic acid group or a ω-carboxylic acid isoster such as tetrazol or —SO3H.
US 2010/0305032 discloses compounds comprising polypeptide, e.g., glucagon-like-peptide-1 (GLP-1), derivatives, linked through hydrophilic spacers to albumin binding residues comprising a lipophilic residue; a residue negatively charged at physiological pH; or a residue comprising a group, e.g., —COOH or —SO3H, which can be negatively charged. As stated in this publication, these compounds have protracted profile of action in vivo.
WO 2010/140148 discloses LCFA-like albumin-binding probes containing a spontaneously hydrolysable bond, e.g., HOOC—(CH2)15—S-MAL-FMS-OSu, which efficiently associate with albumin and it is thus capable of converting short-lived amino-containing peptides and proteins to inactive reactivable prodrugs having prolonged lifetime profiles in vivo, without the drawback of inactivation that often occurs upon such derivatization. According to this technology, the drug conjugated with said probe is converted, upon administration and following association with albumin, into a long-lived prodrug, which gradually releases the pharmacologically active constituent under physiological conditions. As stated in this publication, these probes may comprise an acidic group different than —COOH, in particular, —SO3H or —O—PO3H2 group.